Nanoparticle Therapy Shows Promise in Treating Pancreatic Cancer

Scientists from Tel Aviv University (TAU), the Chaim Sheba Medical Center, and the University of Maryland say they have shed light on the inverse correlation between an oncogene and the expression of an oncosuppressor microRNA (miRNA) as the reason for extended pancreatic cancer survival. The researchers believe their work can lead to the development of a drug cocktail for this deadly disease and other cancers.

The study (“Amphiphilic Nanocarrier-Induced Modulation of PLK1 and miR-34a Leads to Improved Therapeutic Response in Pancreatic Cancer”) was published in Nature Communications.

“The heterogeneity of pancreatic ductal adenocarcinoma (PDAC) suggests that successful treatment might rely on simultaneous targeting of multiple genes, which can be achieved by RNA interference-based therapeutic strategies. Here we show a potent combination of microRNA and siRNA delivered by an efficient nanocarrier to PDAC tumors. Using proteomic-microRNA profiles and survival data of PDAC patients from TCGA, we found a novel signature for prolonged survival. Accordingly, we used a microRNA-mimic to increase miR-34a together with siRNA to silence PLK1 oncogene,” write the investigators.

“For in vivo dual-targeting of this combination, we developed a biodegradable amphiphilic polyglutamate amine polymeric nanocarrier (APA). APA-miRNA–siRNA polyplexes systemically administered to orthotopically inoculated PDAC-bearing mice showed no toxicity and accumulated at the tumor, resulting in an enhanced antitumor effect due to inhibition of MYC oncogene, a common target of both miR-34a and PLK1. Taken together, our findings warrant this unique combined polyplex’s potential as a novel nanotherapeutic for PDAC.”

The overwhelming majority of pancreatic cancer patients die within just a year of diagnosis, notes Ronit Satchi-Fainaro, Ph.D., chair of the department of physiology and pharmacology at TAU's Sackler Faculty of Medicine. “Despite all the treatments afforded by modern medicine, some 75% of all pancreatic cancer patients die within 12 months of diagnosis, including many who die within just a few months,” she continues. “But around 7% of those diagnosed will survive more than five years. We sought to examine what distinguishes the survivors from the rest of the patients.”

The research team examined pancreatic cancer cells and discovered an inverse correlation between the signatures of miR-34a, a tumor suppressant, and PLK1, a known oncogene. The levels of miR-34a were low in pancreatic cancer mouse models, while the levels of the oncogene were high. This correlation made sense for such an aggressive cancer. But the team needed to see if the same was true in humans.

The scientists performed RNA profiling and analysis of samples taken from pancreatic cancer patients. The molecular profiling revealed the same genomic pattern found earlier in mouse models of pancreatic cancer.

The scientists then created a nanoparticle that selectively delivers genetic material to a tumor and prevents side effects in surrounding healthy tissues.

“We designed a nanocarrier to deliver two passengers: miR-34a, which degrades hundreds of oncogenes, and a PLK1 small interfering RNA (siRNA), which silences a single gene,” says Dr. Satchi-Fainaro. “These were delivered directly to the tumor site to change the molecular signature of the cancer cells, rendering the tumor dormant or eradicating it altogether.

“The nanoparticle is like a taxi carrying two important passengers. Many oncology protocols are cocktails, but the drugs usually do not reach the tumor at the same time. But our 'taxi' kept the 'passengers'—and the rest of the body—safe the whole way, targeting only the tumor tissue. Once it 'parked,' an enzyme present in pancreatic cancer caused the carrier to biodegrade, allowing the therapeutic cargo to be released at the correct address—the tumor cells.”

The researchers injected the nanoparticles into pancreatic tumor-bearing mice and observed that by balancing these two targets—bringing them to a normal level by increasing their expression or blocking the gene responsible for their expression—they significantly prolonged the survival of the mice.

“This treatment takes into account the entire genomic pattern and shows that affecting a single gene is not enough for the treatment of pancreatic cancer or any cancer type in general,” explains Dr. Satchi-Fainaro.